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Saturday, November 10, 2012

β-THALASSAEMIA

This is prevalent throughout
tropical and north Africa, Mediterranean, Middle East and South-east Asia,
including India. Over 200 different mutations of the β globin gene or its
promoter are known to cause β thalassaemia, the majority being single nucleotide
substitution (point mutations). Each mutation is linked to specific pattern of
RFLPs within β globin gene cluster (or haplotype). In severe forms of β
thalassemia (β thalassemia major) there is severe impairment or absence of β
chain production. As a consequence excess α chain accumulates and precipitates
in red cell precursors leading to their destruction within bone marrow leading
to ineffective erythropoiesis. Also there is hemolysis in mature red cells due
to inclusions.

Red cell containing fetal Hb survives preferentially since there
is less globin chain imbalance. The anaemia produces tissue hypoxia, which
stimulates erythropoietin production and massive expansion of erythropoiesis in
bone marrow and extramedullary sites.

If untreated, β thalassemia major
leads to severe anaemia, wasting and growth retardation, with death in early
childhood. As a result of expansion in erythropoiesis there are bone
deformities and enlargement of liver and spleen. Widening of the dipole of the facial
bones and skull gives rise to a characteristic thalassaemic facies, splaying of
the teeth and frontal bossing.

The
treatment of β thalassemia major is regular blood transfusion to maintain Hb
between 10-14 g/dL. But inevitable complication of multiple transfusions is
iron overloading. If untreated this leads to haemosiderosis which causes
multisystem dysfunction due to abnormal accumulation of iron in tissues.
Vitamin C enhances the urinary excretion of iron, so patients receiving iron
chelating agents like desferrioxamine to see the efficacy of chelation and is
done by measuring ferritin.

Allogenic bone marrow
transplantation from HLA matched siblings has been used with considerable
success for treatment of β thalassemia major with disease free survival rates
up to 95% in younger children.

Mutations that severely disrupts or
abolish β globin synthesis (β0 thalassaemia) includes those that
prevent normal splicing of mRNA (splice junction or splice site mutations) or
generate a non-functional mRNA by premature translation termination (nonsense
mutations), and mutation that partially disrupts or reduced β globin synthesis
(β+, β++ thalassemia) includes small nucleotide deletions
or insertions leading to frameshift mutations.

β-thalassaemia can be co-inherited
with α-thalassemia and leads to imbalance in globin chain synthesis and results
in more ineffective erythropoiesis, and hereditary persistence of fetal
hemoglobin (HPFH). HPFH can be linked to β globin cluster, and includes large
deletions and point mutations in promoter regions of the γ globin genes. The heterozygous
(carrier) state for β thalassaemia (β thalassaemia trait) is usually without
harmful effects.

Most individuals have slightly reduced Hb concentrations and
elevated red cell count. A raised HbA2 concentration is an important
diagnostic marker and distinguishes β thalassaemia trait from α thalassemia, in
which HbA2 is normal or low. This reflects during β thalassemia
there is high output from δ globin
gene. Similarly HbF levels are frequently slightly raised in β thalassemia
heterozygotes.

Sometimes called Cooley’s anaemia
after the physician who in 1925 first described the condition in children of
Italian and Greek immigrants in New York. This condition results from mutation
that interferes with translation, in about 50% of all mutations. There is also
frame shift or non sense mutation that prematurely terminates β-globin chain.

Clinical presentation is usually at
<1 year of age with features that includes failure to grow, abdominal girth
expansion, and failure to thrive. There is frontal bossing (rounded eminence on
forehead), pallor, etc. These features are due to marrow expansion caused by
ineffective erythropoiesis with production of highly unstable α-globin
tetramers leading to increased plasma volume and formation of extramedullary erythropoietic
tissue.

Typical CBC results include severe
anemia with Hb between 3-6.5 g/dL, MCV <72 fL, and MCHC <320 g/L. There
is microcytosis, target cells, polychromasia, nucleated red cells,
anisocytosis. There is major HbF band with absence of HbA band and variable HbA2
(1-6%).

Electrophoresis at alkaline and acid pH shows dominant band in F
position.

β-thalassemia (β-thalassemia Intermedia):

There is reduced production of
β-globin chain with subsequent reduction in quantity of HbA. There is large HbF
band with reduced HbA. HbA2 is above reference interval. Bands in A
and F positions are seen on electrophoresis. The Hb is significantly reduced
(6-10 g/dL).

β-thalassemia minor (β-thalassemia trait):

The CBC shows low normal or
decreased Hb and hematocrit, decreased MCV (<72 fL) and MCH (<27 pg). PBS
has occasional hypochromia, poikilocytosis, and target cells. The diagnosis of
this minor condition with appropriate indices in CBC, is dependent on finding
of raised HbA2 concentration (>3.5%). Iron deplete individuals
should become iron replete before a definitive diagnosis as HbA2 may
be falsely low in iron deficiency individual. HbF will be raised (>1%).

δβ-Thalassemia:

There is
deletion of δ- and
β-gene. There is increase in HbA with reduced HbA2 and raised HbF.
Hb lepore is sometimes classified as this type of thalassemia due to reduction
in production of both delta and β globin chain or abnormal Hb chain. Thalassemic indices on CBC includes low MCV,
MCH, normal RDW.

Hereditary persistence of Fetal Hemoglobin (HPHF):

This describes the group of
genetic conditions in which the concentration of HbF is increased because of
reduction of β-globin synthesis and compensatory increase in δ-globin synthesis. Here Hb, MCV,
MCH are within reference intervals.